Distinct tumor microenvironments—hypoxic cores, invasive edges, and perivascular regions—harbor glioblastoma-initiating cells (GICs) with unique epigenetic traits that promote radiation evasion: hypoxic cores activate the HIF–SIRT axis to maintain quiescence; invasive edges employ EZH2-mediated H3K27me3 to drive proneural–mesenchymal transition (PMT); and perivascular niches utilize HDAC–DNA repair and BRD4–super-enhancer mechanisms to sustain stemness. Here, EZH2 is linked to glioblastoma.